Role of Nrf2 during cholestsis and gallstone formation

描述(由申请人提供) 胆结石疾病影响着3000多万美国人，导致美国每年有超过75万人接受胆囊切除术。胆结石可通过阻塞胆总管引起肝外胆汁淤积。在胆汁中，胆汁酸和磷脂对胆固醇的增溶很重要。当胆汁成分发生变化，导致胆汁酸与胆固醇的比率降低(胆汁酸合成减少和/或胆汁中胆固醇分泌增加)时，形成胆固醇结石的可能性增加。这项建议的主要目标是了解转录因子核因子-E2相关因子2(NRF2)如何在胆汁淤积和高胆固醇饮食期间调节胆固醇和胆汁酸的代谢和处置。初步研究表明，在胆汁淤积过程中，肝脏转运蛋白的表达与野生型(WT)小鼠和Nrf2缺失小鼠不同。因此，特定的目标1将在这些初步发现的基础上进行扩展，并确定在胆汁淤积期间WT和Nrf2基因缺失的小鼠之间的药物处置是否不同。重要的是，初步研究还表明，与WT小鼠相比，Nrf2基因缺失的小鼠肝脏和血清中的胆汁酸水平降低，这表明Nrf2对胆汁酸的合成很重要。因此，特异性靶点2将决定Nrf2调节肝脏胆汁酸水平的机制。初步数据还表明，当暴露在高胆固醇饮食中时，Nrf2基因缺失的小鼠显示出胆固醇结石的形成增加，而针对特定目标3的研究将确定Nrf2基因缺失的小鼠更容易形成胆结石的机制。目标3中的研究将检查胆汁胆固醇、胆汁酸和磷脂分泌，以及检查胆固醇和胆汁酸合成、代谢和处置基因在肝脏表达的差异。总之，拟议的研究将提供关于肝脏调节胆固醇和胆汁酸的新信息，并为胆结石形成的机制提供有价值的见解。

DESCRIPTION (provided by applicant) Gallstone disease affects more than 30,000,000 Americans and results in more than 750,000 cholecystectomies in the United States annually. Gallstones can cause extrahepatic cholestasis by occluding the common bile duct. In bile, bile acids and phospholipids are important for the solubilization of cholesterol. When the composition of bile changes such that the ratio of bile acids to cholesterol decreases (either decreased bile acid synthesis and/or increased cholesterol secretion into bile), the probability for formation of cholesterol gallstones increases. The broad objective of this proposal is to understand how the transcription factor Nuclear Factor-E2-related factor 2 (Nrf2) regulates cholesterol and bile acid metabolism and disposition during cholestasis and during exposure to a high cholesterol diet. Preliminary studies show that liver transporter expression is different in livers from wild-type (WT) mice and Nrf2-null mice during cholestasis. Thus, Specific Aim 1 will expand upon these initial findings and determine whether drug disposition differs between WT and Nrf2-null mice during cholestasis. Importantly, preliminary studies also demonstrated that bile acid levels are decreased in liver and serum from Nrf2-null mice as compared to WT mice, suggesting that Nrf2 is important for bile acid synthesis. Therefore, Specific Aim 2 will determine the mechanism by which Nrf2 regulates bile acid levels in liver. Preliminary data also indicated that Nrf2-null mice exhibit increased formation of cholesterol gallstones when exposed to a high cholesterol diet, and studies in Specific Aim 3 will determine the mechanism by which Nrf2-null mice are more susceptible to gallstone formation. Studies in aim 3 will examine biliary cholesterol, bile acid, and phospholipid secretion as well as examine differences in heptic expression of genes for cholesterol and bile acid synthesis, metabolism, and disposition. Together, the proposed studies will provide novel information regarding liver regulation of cholesterol and bile acids and provide valuable insight into the pathogenesis of gallstone formation.